Molecules in donated blood can influence the progression of Alzheimer’s-like pathology in the brain, according to a new mouse study. Led by scientists at the Instituto Latinoamericano de Salud Cerebral (BrainLat) at Universidad Adolfo Ibáñez, Chile, the study examined whether circulating factors outside the brain could modulate disease-associated changes.
Using Tg2576 transgenic mice, which overexpress human amyloid precursor protein, the team administered weekly infusions of whole blood from either young or old wild-type donor mice over a 30-week period. Cognitive performance was assessed using the Barnes maze: a test of spatial memory. Mice receiving blood from older donors showed significantly impaired short- and long-term memory compared with those infused with young blood.
Histological analysis further revealed increased amyloid-β (Aβ) deposition in the cerebral cortex of mice treated with aged blood, detected by immunohistochemistry using the 4G8 antibody. In contrast, mice receiving young blood exhibited lower amyloid burden in these regions.
To investigate molecular changes associated with these effects, the researchers carried out a large-scale proteomic analysis of brain tissue. High-resolution mass spectrometry enabled quantification of more than 3,300 proteins, with 256 showing differential expression between treatment groups. Pathway analysis linked these changes to synaptic signaling, endocannabinoid pathways, and calcium-dependent neuronal regulation.
One protein highlighted by the analysis was the α2δ2 subunit of voltage-gated calcium channels (CACNA2D2), which was upregulated in mice infused with aged blood and validated by western blotting. The authors suggest that altered expression of this protein may contribute to synaptic dysfunction and impaired neuronal communication.
MELISA Institute contributed to the proteomic component of the study, using a trapped ion mobility spectrometry–time-of-flight platform to generate the dataset. “Within this study, we conducted a large-scale proteomic analysis that allowed us to generate excellent quality data in this complex matrix like plasma, a technical challenge for any proteomics laboratory,” said Mauricio Hernández, a proteomics specialist at MELISA Institute, in a press release.
According to senior author Claudia Durán-Aniotz, the results highlight the importance of systemic influences on neurodegeneration. “By demonstrating that peripheral signals derived from aged blood can modulate central processes in the pathophysiology of Alzheimer’s, these findings open new opportunities to study therapeutic targets aimed at the blood–brain axis.”
The authors emphasize that further work will be needed to identify the specific circulating factors responsible and to assess whether similar mechanisms operate in humans.
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